Understanding the molecular basis of hybrid sterility and hybrid inviability is a fundamental problem in speciation, the process by which one species splits into two. Studying hybrid dysfunction also provides a unique route to identifying genes that, despite functioning in essential cellular processes, evolve rapidly between species. Our goal is to understand the genetic and molecular bases of speciation in Drosophila using a highly multidisciplinary approach. In particular, my laboratory is interested in addressing the following questions: First, what are genes that underlie the sterility and inviability in hybrids between Drosophila species? Second, what are the molecular processes that are disrupted in hybrids? Third, what are the biological forces that drive the rapid evolution of genes that cause hybrid dysfunction? With recent technological advances in next-generation sequencing, genetic engineering, and cell biological approaches, it is now possible to address fundamental questions shrouding the molecular basis of speciation. First, my laboratory has designed a new genomics-based approach to efficiently identify hybrid sterility and hybrid inviability genes. We used this novel approach to successfully identify a new hybrid incompatibility gene, which is essential for mediating hybrid male inviability between D. melanogaster and D. simulans. We are studying the role of this gene in the cellular response to DNA damage, a process that is of critical importance in cancer biology. Second, we performing experiments to understand the function of Overdrive, a gene that we discovered for its essential role in both segregation distortion and male sterility in hybrids between the Bogota and USA subspecies of D. pseudoobscura. My laboratory is using genetic and cell biological approaches to understand the function of Overdrive in the meiotic chromosomal segregation. We are developing new tools to understand the developmental mechanisms in the germline that respond to errors in chromosomal segregation during meiosis, a process that has fundamental implications for the causes of birth defects. This line of work is also providing insights into the molecular mechanisms of segregation distortion. Lastly, we are using our new approach to identify the genes that interact with Overdrive to cause hybrid sterility and segregation distortion in hybrids between the Bogota and USA subspecies of Drosophila pseudoobscura. This represents a major step forward in gaining a complete picture of the genes and molecular processes that are important in the earliest stages of speciation, and provides an unprecedented opportunity to examine the role of segregation distorters as a driving force in the evolution of hybrid sterility. Together, these experiments will establish the Bogota-USA subspecies of D. pseudoobscura as one of the best-understood cases in speciation at the genetic, molecular and evolutionary levels.